Host guanylate binding proteins participate in parasite control during Leishmania infection

Abstract

Abstract Cutaneous leishmaniasis (CL) is a debilitating neglected tropical disease causing lesions ranging from self-healing to permanent disfigurations. A predominant Th1 response relying on IFNγ production leads to parasite control during CL. Although IFNγ is mainly responsible for activating macrophages to produce NO leading to parasite control, IFNγ can activate other downstream pathways involved in cell autonomous immunity including the activation of guanylate binding proteins (GBPs), a class of interferon-inducible GTPases. GBPs play a role in host defense against some intracellular pathogens, but minimal work has been done to understand the role of GBPs during Leishmania infection. Utilizing RNA-Seq we found several GBPs are upregulated in lesions during L. major infection in mice. Single-cell RNA-Sequencing revealed macrophages as the main cell type expressing Gbps, including Gbp2, Gbp5, and Gbp7 during infection. Additionally, Gbp expression was not unique to L. major infection; both L. amazonensis and L. mexicana infection in vivo resulted in elevated Gbp expression. Preliminary in vitro experiments show macrophages from GBPChr3 KO mice harbor increased numbers of parasites compared to control macrophages with and without IFNγ treatment. Consistent with in vitro findings, infected GBPChr3 KO mice exhibit increased pathology compared to control mice. Together these data suggest GBPs participate in the defense against Leishmania parasites.